Protease-Activated Receptors in Neuronal Development, Neurodegeneration, and Neuroprotection: Thrombin as Signaling Molecule in the Brain

Abstract

Protease-activated receptors (PARs) belong to the superfamily of seven transmembrane domain G protein-coupled receptors. Four PAR subtypes are known, PAR-1 to -4. PARs are highly homologous between the species and are expressed in a wide variety of tissues and cell types. Of particular interest is the role which these receptors play in the brain, with regard to neuroprotection or degeneration under pathological conditions. The main agonist of PARs is thrombin, a multifunctional serine protease, known to be present not only in blood plasma but also in the brain. PARs possess an irreversible activation mechanism. Binding of agonist and subsequent cleavage of the extracellular N-terminus of the receptor results in exposure of a so-called tethered ligand domain, which then binds to extracellular loop 2 of the receptor leading to receptor activation. PARs exhibit an extensive expression pattern in both the central and the peripheral nervous system. PARs participate in several mechanisms important for normal cellular functioning and during critical situations involving cellular survival and death. In the last few years, research on Alzheimer's disease and stroke has linked PARs to the pathophysiology of these neurodegenerative disorders. Actions of thrombin are concentration-dependent, and therefore, depending on cellular function and environment, serve as a double-edged sword. Thrombin can be neuroprotective during stress conditions, whereas under normal conditions high concentrations of thrombin are toxic to cells.

Activity of recombinant trypsin isoforms on human proteinase‐activated receptors (PAR): mesotrypsin cannot activate epithelial PAR‐1, ‐2, but weakly activates brain PAR‐1

“…These results together with mesotrypsin's resistance to polypeptide trypsin inhibitors, which are present in the brain as well (Osterwalder et al, 1996), suggest a special physiological role of this trypsin isoform in the human brain. Recently, it was recognized that neuronal PARs play roles in neurogenic inflammation and neurodegenerative processes, as well as in nociception (reviewed in Vergnolle et al, 2003;Rohatgi et al, 2004). PAR-1 localization and function were explored not only in rodent but also in human brain (Junge et al, 2004).…”

Thrombin Cleavage of Inter-α-inhibitor Heavy Chain 1 Regulates Leukocyte Binding to an Inflammatory Hyaluronan Matrix

“…In addition to hemostasis, thrombin also has roles in tissue repair (30), development (31), and in inflammation (32). Many of the effects of thrombin on platelets and endothelial cells are elicited through interaction with a family of transmembrane G-protein-coupled receptors, termed protease-activated receptors (PARs) (33).…”

Coagulation factor Xa activates thrombin in ischemic neural tissue

“…In cell culture models, both TPC and thrombin-induced cell death are mediated by protease-activated receptor-1 (PAR-1) (Donovan et al 1997;Donovan and Cunningham 1998;Rohatgi et al 2004). It is becoming increasingly clear that thrombin is involved in cell death and survival pathways also in the brain (Xi et al 2003).…”

“…It is becoming increasingly clear that thrombin is involved in cell death and survival pathways also in the brain (Xi et al 2003). Prothrombin mRNA (Dihanich et al 1991), the thrombin receptors PAR-1, -3, and -4, and the thrombin inhibitor protease nexin-1 (PN-1) are expressed in neural cells (for review, Rohatgi et al 2004). Hirudin, a potent thrombin inhibitor reduced ischemic damage in ischemic stroke models both in vivo (Striggow et al 2000;Karabiyikoglu et al 2004) and in organotypic hippocampal slice cultures subjected to oxygen and glucose deprivation (OGD) (De Castro Ribeiro et al 2006).…”